The newly arising field of AllergoOncology is based upon observations and studies showing that those individuals with raised levels of IgE (e.g. individuals who suffer from allergies) are much less likely to suffer from certain types of cancer. Researchers in this field are exploring the therapeutic potential of the IgE antibody class in the prevention and treatment of certain cancers.
IgE antibodies mediate allergic and asthmatic reactions, characterized by immediate hypersensitivity, followed by an inflammatory delayed type response requiring the recruitment of effector cells. The uniqueness of the allergic reaction is due to the presence of mast cells and Langerhans/dendritic cells in the tissue that are sensitized by the IgE bound to the high-affinity FcεRI (Kinet, J P, Annu. Rev. Immunol., 17:931-72: 931-972 (1999); and Ravetch J V, and Kinet J P, Annu. Rev. Immunol., 9: 457-492 (1991)). The activated Langerhans/dendritic cells migrate to local lymph nodes and stimulate cognate T cells, which migrate to the tissue, participate in the inflammatory response and stimulate antibody synthesis. IgE bound to mast cells and basophils can cause degranulation of the cells, but it requires cross-linking by the antigen the IgE recognizes. Following the acute phase of recruitment, eosinophils are recruited in the late-phase reaction. Activated eosinophils are strong mediators of antibody-dependent cell-mediated cytotoxicity (ADCC) via toxic granule proteins and cause tissue damage via pro-inflammatory cytokines and vasoactive lipid mediators (leukotrienes, prostaglandin D2, platelet-activating factor). The processing of the IgE containing immune complex by Langerhans cells and dendritic cells is a critical step for the induction of the late-phase reaction. Activated T helper cells generate IL-4 and IL-5, which in turn recruits and activates eosinophils causing ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) (Kinet, J P, Annu. Rev. Immunol., 17:931-72: 931-972 (1999); Maurer, D., et al., J. Immunol., 161: 2731-2739 (1998) and Maurer D., et al., J. Immunol., 154: 6285-6290 (1995)).
While B cells can recognize antigen in its native conformation, T cells generally recognize antigen that has been “processed” by antigen presenting cells (APCs) and then presented on the surface of the cell by major histocompatibility complex (MHC) molecules (Peakman, M. and Vergani, D., New York: Churchhill Livingston; (1997)). MHC molecules are receptors for peptide antigens. There are two classes of MHC molecules, termed MHC class I and MHC class II. Although united in their function of peptide antigen presentation and contact points for T cells, the differences in the structure and intracellular trafficking of the two types are critical because among other things, they elicit very different immune responses. A major obstacle in the creation of effective tumor immunity is that typically, there is poor presentation of tumor antigen on MHC class I and class II molecules together (cross-presentation). Dendritic cells are bone marrow-derived leukocytes that are more potent initiators of T cell-dependent immune responses than any other antigen presenting cells that have been tested (Peakman, M. and Vergani, D., New York: Churchhill Livingston (1997)). Unlike other APCs, dendritic cells can acquire antigens from their environment and process them for cross-presentation, allowing activation of both CD8+ and CD4+ T cells. However, this process requires high antigen concentrations. Simultaneous presentation on MHC II provides for T helper cell activation. Depending on the stimuli, either production of cytokines IL-12 and IFN-γ by T helper (Th) cell 1 type and cytotoxic T-lymphocyte (CTL) induction occurs (collectively referred to herein as the “Th1/Tc1 immune response); or IL-4, IL-5 and IL-10 is produced by Th2 cells for B cell help (referred to herein as “Th2 immune response”). An important factor in immune induction is the activation or maturation of the APC, which induces the expression of co-stimulatory molecules that are necessary to engage the T cell.
It is now believed that the engagement of the toll-like receptor (TLR) family (Okamoto, M. and Sato, M., J. Med. Invest., 50: 9-24 (2003)) as well as other receptors including Fc receptors (Hamano, Y., et al., J. Immunol., 164: 6113-6119 (2000) and Regnault, A., et al., The Journal of Experimental Medicine, 189: 371-380 (1999)) mediates activation and maturation of macrophages and dendritic cells, which is crucial for activating the innate immune system. Fc receptors have also been shown to facilitate antigen uptake and presentation. Among others, we have shown that immune complexed (IC)-pulsed dendritic cells induce stronger CD4+ and CD8+ T cell responses as compared to dendritic cells pulsed with PSA alone (Berlyn, K A, et al., Clin. Immunol., 101: 276-283 (2001)). Similarly, NY-ESO-1 as well as ovalbumin or pyruvate dehydrogenase are all presented to T cells much more efficiently when captured as an immune complex rather than as free-antigen (Regnault A., et al., The Journal of Experimental Medicine 189:371-380 (1999); Nagata Y., et al., Proc. Natl. Acad. Sci. U.S.A., 99: 10629-10634 (2002); Kita, H., et al., J. Exp. Med., 195:113-123 (2002) and Schuurhuis, D H, et al., J. Immunol., 168: 2240-2246 (2002)). The results suggest that effective cancer vaccines may be generated by administering antibodies that target circulating antigen and form immune complex that target dendritic cells in vivo.
IgE binds to two types of Fc receptors, called FcεRI (or high-affinity FcεR) (Ka=1011 M−1) and FcεRII (or low-affinity FcεR, CD23) (Ka<108 M−1). Therefore, unlike antibodies of the IgG class, IgE binds to its FcεRI with extremely high affinity which in the case of FcεRI is about 3 orders of magnitude higher than that of IgG for the FcRs (FcγRI-III) and in the case of FcεRII is similar to the affinity of IgG for its high affinity FcγRI (Gould, H J, et al., Annu. Rev. Immunol., 21: 579-628. Epub@2001 Dec@19.:579-628 (2003); Gounni, A S, et al., Nature, 367: 183-186 (1994); Kinet, J P, Annu. Rev. Immunol., 17: 931-972 (1999) and Ravetch J V, and Kinet J P, Annu. Rev. Immunol., 9: 457-492 (1991)). Because the IgE concentration in normal serum is usually very low (less than 1 μg/mL), the FcεR are typically available for occupancy if IgE is induced by allergies and parasitic infestation or if administered. The FcεRI is composed of four polypeptide chains, one α, one β, and two γ chains. The α chain contains the IgE binding site and is a member of the immunoglobulin supergene family. The FcεRII consists of one polypeptide chain which shows homology to animal lectin receptors. FcεRI is expressed on mast cells and basophils as well as Langerhans cells and dendritic cells where it is involved in antigen presentation, on eosinophils where it plays a role in defense against parasitic infection, and also on monocytes (see Kinet, J P, Annu. Rev. Immunol., 17: 931-72:931-972 (1999) for a review). Crosslinking of the FcεRI receptors via bridging of bound IgE induces immediate release of mediators of inflammation such as histamine, various cationic proteases, leukotrienes, prostaglandin E2, or β-glucuronidase, and delayed secretion of IL-4, 5, and 6. FcεRII is a member of the Ig superfamily, more widely expressed on resting and mature B cells, monocytes, follicular dendritic cells, macrophages, eosinophils, platelets, Langerhans cells, and a subset of T cells (10-15% of tonsillar T cells). IL-4 up-regulates FcεRII expression on B cells and macrophages. FcεRII on macrophages, eosinophils, and platelets mediates ADCC to schistosomules, enhance phagocytosis, and induce the release of granule enzymes (Gounni, A S, et al., Nature, 367: 183-186 (1994); Kinet, J P, Annu. Rev. Immunol., 17: 931-972 (1999) and Spiegelberg, H L, J. Invest. Dermatol., 94: 49S-52S (1990)). FcεRII is involved in both IgE regulation and allergen presentation by B-cells, but understanding the functional roles of CD23 is further complicated by the fact that it exists both as a cell surface molecule and in a soluble form generated by cleavage from the cell surface; furthermore, it exists in both monomeric and oligomeric states (see Gould, H J, and Sutton, B J, Nat. Rev. Immunol., 8:205-217 (2008) for a review). CD23 responds to high levels of IgE by downregulating IgE secretion. In human monocytes, CD23 triggering results in release of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, IL-1, IL-6, and granulocyte/macrophage-colony stimulating factor (GM-CSF). IL-4 appears to play a central role in immediate-type hypersensitivity. It induces human B cells to secrete IgE and IgG4 and activated T helper cells. IL-4 also stimulates mast cell growth and up-regulates FcεRII expression.
Most of the antibodies used in the treatment of cancer, including FDA approved antibodies such as trastuzumab (HERCEPTIN®) and rituximab (RITUXAN®)), are of the IgG class (Carter, P., IBC's Tenth International Conference. 6-9 Dec. 1999, La Jolla, Calif., USA. IDrugs. 3:259-261 (2000); Carter, P., Nat. Rev. Cancer, 1: 118-129 (2001) and Carter, P J, Nat. Rev. Immunol., 6: 343-357 (2006)). However, four monoclonal IgE antibodies specific for tumor antigens have been reported. The application of IgE for the therapy of cancer was pioneered by Nagy et al. (Nagy, E., et al., Cancer Immunol. Immunother., 34: 63-69 (1991)), who developed a murine IgE monoclonal antibody specific for the major envelope glycoprotein (gp36) of mouse mammary tumor virus (MMTV) and demonstrated significant anti-tumor activity in C3H/HeJ mice bearing a syngeneic MMTV-secreting mammary adenocarcinoma (H2712) (Nagy, E., et al., Cancer Immunol. Immunother., 34: 63-69 (1991)). Kershaw et al. (Kershaw, M H, et al., Oncol. Res., 10: 133-142 (1998)) developed a murine monoclonal IgE named 30.6, specific for an antigenic determinant expressed on the surface of colorectal adenocarcinoma cells. Mouse IgE 30.6 inhibited the growth of established human colorectal carcinoma COLO 205 cells growing subcutaneously in severe combined immune deficient (SCID) mice, although this effect was transient. By contrast, a mouse IgG 30.6 and a mouse/human chimeric IgE 30.6 did not show anti-tumor effects. The mouse IgE specific effect was attributed to the interaction of the antibody with FcεR bearing effector cells since the activity was specifically abrogated by prior administration of a nonspecific mouse IgE (Kershaw, M H, et al., Oncol. Res., 10: 133-142 (1998)). The lack of effect exhibited by the mouse/human chimeric IgE 30.6 is explained by the fact that mouse FcεRI binds mouse IgE, but not human IgE. Gould et al. (Gould, H J, et al., Eur. J. Immunol., 29: 3527-3537 (1999)) developed a mouse/human chimeric IgE (MOv18-IgE) and IgG MOv18 (IgG1) specific for the ovarian cancer tumor associated antigen folate binding protein (FBP). The protective activities of MOv18-IgE and MOv18-IgG1 were compared in a SCID mouse xenograft model of human ovarian carcinoma (IGROV1). Mice were reconstituted with human peripheral blood mononuclear cells (PBMC) to provide the model with effector cells capable of binding human IgE constant regions. The beneficial effects of MOv18-IgE were greater and of longer duration than those of MOv18-IgG1 demonstrating the superior anti-tumor effects of IgE antibodies (Gould, H J, et al., Eur. J. Immunol., 29: 3527-3537 (1999)). In addition, the group of Gould et al. recently demonstrated for the first time monocyte-mediated IgE-dependent tumor cell killing by two distinct pathways, ADCC and phagocytosis (ADCP), mediated through FcεRI and FcεRII (Karagiannis, S N, et al., Cancer Immunol. Immunother., 57: 247-263 (2008) and Karagiannis, S N, et al., J. Immunol., 179: 2832-2843 (2007)). This group has also used this assay system to make a preliminary assessment of bioactivity of an anti-Her2 IgE construct (Karragiannis, P., Cancer Immunol and Immunother (2008) epub ahead of print). Since human PBMC are short-lived in SCID mice the inventors have postulated that the anti-tumor effect will be enhanced in humans where the supply of effector cells would be permanent. None of the studies could address the capacity of the mouse/human chimeric IgE to elicit an adaptive immune response due to the fact that murine APCs such as dendritic cells do not express the FcεRI (Kinet, J P, Annu. Rev. Immunol., 17: 931-72:931-972 (1999)).
Relevant epidemiological studies on the association of allergic diseases with cancer support a lower risk of cancer among people with a history of allergies or high levels of serum IgE including different hematopoietic malignancies (Grulich, A E and Vajdic, C M, Pathology, 37: 409-419 (2005); Wang, H. and Diepgen, T L, Allergy, 60: 1098-1111 (2005); Grulich, A E, et al., Cancer Epidemiol. Biomarkers Prey., 16: 405-408 (2007); Turner, M C, et al., Am. J. Epidemiol., 162: 212-221 (2005); Wang, H. and Diepgen, T L, Br., J. Dermatol., 154: 205-210 (2006); Wang, H., et al., Int. J. Cancer, 119: 695-701 (2006); Turner, M C, et al., Int. J. Cancer, 118: 3124-3132 (2006) and Melbye, M., et al., J. Natl. Cancer Inst., 99: 158-166 (2007)) and solid tumors such as ovarian, colorectal, pancreatic cancer, and glioma (Wang, H. and Diepgen, T L, Allergy, 60: 1098-1111 (2005); Turner, M C, et al., Am. J. Epidemiol., 162: 212-221 (2005); Wang, H., et al., Int. J. Cancer, 119: 695-701 (2006); Turner, M C, et al., Int. J. Cancer, 118: 3124-3132 (2006); Mills, P K, et al., Am. J. Epidemiol., 136: 287-295 (1992); Wiemels, J L, et al., Cancer Res., 64: 8468-8473 (2004) and Wrensch, M., et al., Cancer Res., 66: 4531-4541 (2006)).
Furthermore, mice infested with nematodes are resistant to syngeneic mammary adenocarcinoma and show lower incidence of spontaneous mammary tumors (Ogilvie, B M, et al., Lancet., 1: 678-680 (1971) and Weatherly, N F, J. Parasitol., 56: 748-752 (1970)). Eosinophilia, either in peripheral blood or tumor-associated tissue, is frequently associated with some tumor types and also found after immunotherapy with IL-2, IL-4, GM-CSF, and antibody to CTLA-4 (Lotfi, R, et al., J. Immunother., 30: 16-28 (2007). Within several tumor types including gastrointestinal tumors, this observation is associated with a significantly better prognosis, whereas their presence in rejecting allografts is largely seen as a harbinger of poor outcome (Lotfi, R. and Lotze, M T, J. Leukoc. Biol., 83: 456-460 (2008)). Matta et al. (Clin Cancer Res 13: 5348-5354 2007) have reported that multiple myeloma patients with relatively higher IgE levels had a better survival than patients with lower levels of IgE. Importantly, this is clearly reflected on the levels of IgE and not the other classes of immunoglobulins. These studies are consistent with a natural role of IgE in the immunosurveillance of cancer including multiple myeloma. Fu, et al. (Clin Exp Immunol 153: 401-409 (2008)) demonstrated that antibodies of the IgE class isolated from pancreatic cancer patients mediate antibody-dependent cell-mediated cytotoxicity against cancer cells.
Finally, treatment with omalizumab (XOLAIR®), which decreases free IgE in serum and down-regulates IgE receptors in effector cells to dampen IgE-mediated inflammatory response, appears to lead to a higher chance of developing cancer. Approximately 1 in 200 treated asthmatic patients developed breast, prostate, melanoma, non-melanoma skin, or parotid gland malignancies during the median observation period of 1 year while in the control group the incidence was 1 in 500 (Dodig, S., et al., Acta Pharm., 55: 123-138 (2005)). These studies suggest a natural role of IgE in the immunosurveillance of cancer.
The art has established methods to treat patients who have developed hypersensitivity reactions to chemotherapeutic agents as well as monoclonal antibodies used in the treatment of autoimmune disease and malignancy in which a rush desensitization to the therapeutic agent is performed (Castells et al., J. Allergy Clin. Immunol. (2008) 122:574). Castells describes a protocol that reduces immunogenicity to an IgG class therapeutic antibody by administering increasing amounts of subtherapeutic dosages to achieve desensitization to the IgG therapeutic over a 4-8 hour period. It is noteworthy that the typical starting concentration for a desensitization protocol with Rituxan is 0.034 mg/mL reflecting the high antibody doses required to achieve clinical effects with IgG1 class cancer targeting antibodies. The art does not address the use of IgE monoclonal antibodies as therapeutic agents or methods for mitigating hypersensitivity reactions when IgE monoclonals are used.